Saha Kamalika, Fisher Matthew L, Adhikary Gautam, Grun Daniel, Eckert Richard L
Department of Biochemistry and Molecular Biology.
Department of Dermatology.
Carcinogenesis. 2017 Aug 1;38(8):827-836. doi: 10.1093/carcin/bgx044.
Protein arginine methyltransferase 5 (PRMT5) cooperates with methylosome protein 50 (MEP50) to arginine methylate histone H3 and H4 to silence gene expression, and increased PRMT5 activity is associated with enhanced cancer cell survival. We have studied the role of PRMT5 and MEP50 in epidermal squamous cell carcinoma. We show that knockdown of PRMT5 or MEP50 results in reduced H4R3me2s formation, and reduced cell proliferation, invasion, migration and tumor formation. We further show that treatment with sulforaphane (SFN), a cancer preventive agent derived from cruciferous vegetables, reduces PRMT5 and MEP50 level and H4R3me2s formation, and this is associated with reduced cell proliferation, invasion and migration. The SFN-dependent reduction in PRMT5 and MEP50 level requires proteasome activity. Moreover, SFN-mediated responses are partially reversed by forced PRMT5 or MEP50 expression. SFN treatment of tumors results in reduced MEP50 level and H4R3me2s formation, confirming that that SFN impacts this complex in vivo. These studies suggest that the PRMT5/MEP50 is required for tumor growth and that reduced expression of this complex is a part of the mechanism of SFN suppression of tumor formation.
蛋白质精氨酸甲基转移酶5（PRMT5）与甲基osome蛋白50（MEP50）协同作用，使组蛋白H3和H4精氨酸甲基化以沉默基因表达，而PRMT5活性增加与癌细胞存活率提高相关。我们研究了PRMT5和MEP50在表皮鳞状细胞癌中的作用。我们发现，敲低PRMT5或MEP50会导致H4R3me2s形成减少，以及细胞增殖、侵袭、迁移和肿瘤形成减少。我们进一步表明，用萝卜硫素（SFN）（一种源自十字花科蔬菜的癌症预防剂）处理会降低PRMT5和MEP50水平以及H4R3me2s形成，这与细胞增殖、侵袭和迁移减少相关。SFN依赖的PRMT5和MEP50水平降低需要蛋白酶体活性。此外，强制表达PRMT5或MEP50可部分逆转SFN介导的反应。用SFN处理肿瘤会导致MEP50水平和H4R3me2s形成减少，证实SFN在体内会影响这种复合物。这些研究表明，PRMT5/MEP50是肿瘤生长所必需的，并且该复合物表达降低是SFN抑制肿瘤形成机制的一部分。
